ORIGINAL CONTRIBUTION phenytoin, intravenous

Phenytoin Administration by Constant Intravenous Infusion: Selective Rates of Administration Study objectives: To determine the adequacy of seizure control and the adverse effects of administering an IV loading dose of phenytoin by constant infusion pump. Design: A prospective study of patients presenting with acute onset of seizures. Patients were divided into two groups. Group 1 comprised all patients 50 years of age or younger without a history of atherosclerotic cardiovascular disease (ASCVD). Group 2 comprised all patients older than 50 years or with a history of ASCVD. Setting: A rural community hospital emergency department. Type of participants: Forty-two adult patients. Interventions: Both groups received an IV loading dose of phenytoin at 15 mg/kg. Infusion rates were 50 rag~rain and 25 mg/min for groups i and 2, respectively Cardiac rhythm and vital signs were monitored throughout and after infusion. Measures and main results: Group 2 demonstrated significantly more cardiovascular side effects (hypotension and bradycardia) than did group 1 (Fisher's exact test, P < .05). Conclusion: Phenytoin provided adequate seizure control in both groups. For individuals with ASCVD, IV phenytoin administration rates should not exceed 25 rag~rain. For individuals without ASCVD, phenytoin administration at 50 mg/min appears safe and without significant cardiovascular side effects. [Donovan PJ, Cline D: Phenytoin administration by constant intravenous infusion: Selective rates of administration. Ann Emerg Med February 1991;20:139-142.]

Paul J Donovan, DO, FACEP* North Adams, Massachusetts David Cline, MD, FACEP1Greenville, North Carolina From the Department of Emergency Services, North Adams Regional Hospital, North Adams, Massachusetts;* and the Department of Emergency Medicine, East Carolina University, Greenville, North Carolina.t Received for publication June 27, 1989. Revision received June 27, 1990. Accepted for publication July 12, 1990. Presented at the Society for Academic Emergency Medicine Annual Meeting in San Diego, May 1989. Address for reprints: Paul J Donovan, DO, FACER Department of Emergency Services, North Adams Regional Hospital, North Adams, Massachusetts 01247.

INTRODUCTION Since the introduction of phenytoin sodium for the treatment of convulsive disorders in 1938 by Merrit and Putnam, 1 it has been considered the drug of choice to prevent repetitive seizures and for status epilepticus once the patient has been stabilized. Oral loading is impractical because of the delay in attaining therapeutic levels (six to ten hours), documented treatment failures, and difficulty in administration to patients who have altered levels of consciousness.2, 3 IV loading is the method of choice because it provides rapid therapeutic levels, is easy to administer, and is effective in preventing and interrupting seizure activity. 4 7 Despite these beneficial effects, the safety of IV phenytoin has been questioned because of its occasional serious adverse cardiovascular effects (eg, hypotension, bradycardia, heart block, and cardiac arrest) and its less serious neurologic and local dermatological effects.6, 8 lz Toxicity is related to the solvent in which phenytoin is dissolved (propylene glycol) and possibly to phenytoin itself or to excessive rates of phenytoin administration. Although it has not been determined which individuals may be at risk for developing serious cardiovascular side effects, previous studies have demonstrated that these symptoms occur primarily in older (age of more than 50 years) individuals, and this phenomenon may relate to the increased frequency of atherosclerotic cardiovascular disease (ASCVD) in these individuals.6,8-1o, 13-18 The Food and Drug Administration recommends administering IV phenytoin by manual IV push at a rate of less than 50 mg/min. Recent studies suggest that the rate of complications may be minimized by constant IV

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IV PHENYTOIN Donovan & Cline

infusion of between 20 and 50 rag/ min after dilution with normal saline.S,6A9 The purpose of this clinical study was to test the efficacy (seizure suppression) and cardiovascular side effects of IV phenytoin administration. The maximum recommended administration rate in patients w i t h o u t ASCVD was compared with one half that rate in individuals with presumed or documented evidence of ASCVD. MATERIALS



All adult patients presenting to the emergency department with status epilepticus, acute repetitive seizure, breakthrough seizures, or seizures secondary to other medical problems (eg, infections, neoplasms, or trauma or structural central nervous system lesions) were candidates for this study. Patients experiencing bradycardia, second- or third-degree heart block, hypotension, or alcohol- or drug-related seizures were excluded. P a t i e n t s were d i v i d e d i n t o t w o groups. Group 1 comprised patients 50 years old or younger without a history of ASCVD. Group 2 comprised all patients older than 50 years or with a history of ASCVD, hypertension, congestive heart failure, or ischemic heart disease. History of ASCVD was based on patient interview and previous record, including prior EGG. Preinfusion evaluation for new-onset seizures included a history and physical examination, blood chemistries, ethanol level, ECG, lumbar puncture, and computed tomography scan of the brain. Preinfusion evaluation of a patient already on phenytoin for previous diagnosis of seizures comprised a history, physical examination, and determination of serum p h e n y t o i n , glucose, and e t h a n o l levels. 2o IV phenytoin (15 mg/kg) was given as a "piggy-back" infusion. The total dose was diluted in normal saline to a concentration of 10 mg/mL solution. This solution was administered by a constant infusion pump at a rate of 50 mg/min in group 1 and 25 mg/ rain in group 2. A 0.22-~m filter was placed on the line to remove any potential crystals. This protocol was not modified in patients with detectable subtherapeutic phenytoin levels. Each patient was placed on a cardiac monitor throughout the infusion 52/140

period. Vital signs and a cardiac rhythm strip were taken at the start of the infusion (time zero) and at 15minute intervals until 60 minutes after infusion. If there was intractable irritation or pain at the IV site, a decrease in systolic blood pressure to less than 100 m m Hg or a mean blood pressure decrease of more than 20 m m Hg, sinus bradycardia, second- or third-degree heart block, or widening of the QRS to more than 0.12 second, the infusion rate was decreased from 50 to 25 m g / m i n in group 1 and from 25 to 20 mg/min in group 2. Recurrent seizures during the infusion were treated with diazepam or phenobarbital. Phenytoin levels were determined by fluorescence p o l a r i z a t i o n i m m u n o a s s a y (TDX system) and drawn one hour after infusion. Patients discharged from the ED were asked to return 24 hours later for follow-up phenytoin levels. Proportions of patients in each of the two groups were analyzed by Fisher's exact test. Power analysis was performed for an c~ level of .05, and for proportions from groups with unequal numbers of subjects. The power for detecting a difference in the proportion of cardiovascular side effects in each group was found to be .89. P was significant at < .05. RESULTS

Forty-two patients were entered into the study over a one-year period - 26 in group 1 and 16 in group 2. Mean age of group 1 patients was 32 --- 8 years, and mean age of group 2 patients was 60 + 9 years. The age range was 20 to 87 years, with an equal number of men and women. The most c o m m o n etiology of seizures in previously diagnosed idiopathic seizure patients was medication n o n c o m p l i a n c e (Table 1). Of these 23 patients, 16 had nondetectable phenytoin levels, and the other s e v e n had levels of less t h a n 5 ~g/mL. Thirty-four of 42 patients were discharged from the ED, and eight were admitted. The incidence of side effects in group 2 (three; 18.8%) was greater than in group 1 (none; 0%), which is significant by Fisher's exact test (P < .05). Of the 16 patients in group 2, 11 had a history of ASCVD (by previous record, including ECG). Fourteen of 26 group 1 patients complained of Annals of Emergency Medicine

TABLE l. Etiology of seizures No. el Patients


Idiopathic (noncompliant) Idiopathic (new onset) History of cerebrovascularaccident Cerebrovascularaccident (new onset) Post-traumatic (noncompliant) Post-traumatic (new onset) Other*

23 3 4 4 2 2 4

*Includes lymphomatosis meningitis (one), lupus cerebritis (one), and aseptic meningitis (two).

pain at the site of infusion. Twelve of these 14 described the pain as tolerable, but in two of the 14 the rate of p h e n y t o i n infusion had to be decreased to 25 m g / m i n because of their pain. Three of 16 group 2 patients developed adverse cardiovascular side effects during p h e n y t o i n infusion. These effects are summarized in Table 2. Two patients developed hypotension, and one developed hypotension and bradycardia. In the patient w h o d e v e l o p e d h y p o t e n s i o n and b r a d y c a r d i a , t h e i n f u s i o n was stopped, but the hypotension did not resolve within 15 minutes. After rec e i v i n g 250 mL of IV l a c t a t e d Ringer's over 15 minutes, the patient's blood pressure returned to preinfusion levels. The infusion was terminated with 50 mg of phenytoin loading dose remaining. The junctional bradycardia resolved spontaneously within four hours. Subsequent 12-lead ECGs and cardiac enz y m e s s h o w e d no e v i d e n c e of myocardial ischemia or infarction. The two patients who developed hypotension had gradual resolution (increase in mean blood pressure of more than 20 m m Hg) within ten and 15 minutes after the infusion was stopped. The infusion then was restarted at a rate of 20 mg/min without complications. No prolongation of QRS or QT interval was noted in any group 1 patients. Only patient 2 (Table 2), from group 2, had widening of her QRS from 0.06 to 0.08 second. No patients in group 2 complained of pain at the infusion site. One patient in e.ach group seized during phenytoin infusion and required IV diazepam to terminate the seizure. No patients developed sei20:2 February 1991

iV PHENYTOIN Donovan & Cline

TABLE 2. Characteristics of patients and analysis of cardiovascular side effects One-Hour CardioPostvascular infusion Medical Phenytoin PatientAge Wt (kg) History Level 1 2

73 87

70 45


11.9 30






Mean Blood Blood Pressure Pressures (mm Hg) Decrease Preinfusion Postinfusien (mm Hg) 22 Hypotension 118/88 88/65 Hypotension/ 130/80 50/30 60 junctional bradycardia Hypotension 120/84 102/66 18 Cardiovascular Side Effects

*IHD, ischemic hear[ disease; CHF, congestive head disease; AF, atrial fibrillation,

zures during the one-hour observation period after phenytoin administration, O n e h o u r after i n f u s i o n , phenytoin levels ranged between 10.2 and 30 ~g/mL. Thirty-nine of 42 patients had levelS between 10.2 and 20 ~g/mL, and the other three had levels of 23.5, 25, and 30 ~g/mL, respectively. Patient 2 of group 2 (Table 2) had a level of 30 ixg/mL. Only three of the 34 discharged p a t i e n t s returned for 2 4 - h o u r p o s t i n f u s i o n levels, and only three of eight admitted patients had these levels done. T h i r t y of t h e 34 p a t i e n t s discharged from the ED were contacted by telephone at 24 hours from ED presentation, and none of these patients had experienced a seizure. Three of the eight patients admitted to the hospital had seizures despite continued t h e r a p e u t i c p h e n y t o i n levels at 24 hours after infusion (12.5, 14, and 15 ~g/mL, respectively). All three of these patients required a second chronic anticonvulsant agent. Visual crystallization was not observed in any of the patients' IV tubings. DISCUSSION IV administration of phenytoin is the preferred mode for acute seizure control. Recent studies support Constant IV infusion after dilution with normal saline.4-6,19 Compared with pushing the drug manually, advantages include fewer cardiovascular side effects, less IV site irritation, constant (nonvariable) infusion rate, and r e d u c t i o n in m e d i c a l s t a f f time.4-6, ~9 However, IV phenytoin is associated with significant cardiovascular, neurologic, and dermatologic adverse effects. 4-12 The adverse c a r d i o v a s c u l a r e f f e c t s are w e l l known and include hypotension, cardiac rhythm disturbances, and alteration of the ECG. 4-t~ 20:2 February 1991

Whether such side effects are due to the amount or rate of phenytoin administered, the solvent (propylene glycol and/or ethyl alcohol), the absolute serum level, patient age, preexisting medical illnesses, or a combination of factors has been questioned. Earnest et al administered IV phenytoin (10 to 15 mg/kg) in saline at 25 to 50 rag/rain to 200 ED patients w i t h c o n v u l s i o n s and found t h a t seven had cardiovascular complications. 6 Three patients developed hypotension and bradycardia, and four developed arrhythmias without hypotension. They concluded that complications occurred at higher rates of infusion and that the drug concentra~ t i o n and r a t e of a d m i n i s t r a t i o n should be reduced in patients with known cardiac disease, abnormal preinfusion ECGs, and/or age of more than 60 years. Cranford et al reported t h a t IV phenytoin {10 to 20 mg/kg infused at 50 mg/min in a solution of propylene glycol and ethanol) was administered on 159 occasions to 139 adult patients for the m a n a g e m e n t of seizures. 4 The overall incidence rate of hypotension was less than 25%. Decreasing the rate of infusion led to n o r m a l i z a t i o n of blood pressure. They concluded that the rate of infusion rather than the amount given is critical in producing hypotension. Cloyd et al found that IV administration of phenytoin (18 mg/kg) in either 0.45% or 0.9% sodium chloride at a rate less than or equal to 50 rag/ rain was generally safe, but that rates as low as 5 to l0 rag/rain may be appropriate in elderly patients to minimize the risk of cardiovascular complications, especially hyp0tension, s Barton found that four of 15 young, healthy volunteers developed hypotension, bradycardia, and syncope Annals of Emergency Medicine

w h e n IV p h e n y t o i n (250 mg) was given at a rate equal to or less than 50 rag/rain. 11 Some evidence points to the solvent (propylene glycol) alone as the factor contributing to the adverse cardiovascular effects. Louis et al found that adverse cardiovascular effects after IV infusion of propylene glycol alone were similar to those after propylene glycol with phenytoin. 21 Propylene glycol is used as the solvent because phenytoin is poorly soluble in less alkaline solution (pH adjusted to 11). Previous studies have demonstrated that the adverse cardiovascular effects with IV infusion of phenytoin occur primarily in older individuals. The age-related increase in ASCVD may be at least in part responsible for the apparent increased risk for these side effects in patients more than 50 years old. 8-t~ The prevalence of either clinical or subclinical ASCVD approaches 80% to 85% in the general population after age 50 and may be the common risk factor for side effectsA 4q8 We assumed that patients with known or potential cardiovascular disease were at greater risk for side effects from constant IV infusion of phenytoin. Despite a reduced rate of administration, these patients had significantly more cardiovascular side effects. Renal insufficiency, hepatic dysfunction, drug interactions, or hypoproteinemia could contribute to the noted cardiovascular side effects because any of these conditions can increase the serum concentration of phenytoin. Only patient 2 (from Table 2) had evidence of renal insufficiency (BUN, 38; creatinine, 2.8 rag/ dL). Two of the three patients were on oral medications. There was no evidence of hepatic dysfunction or hypoproteinemia in these patients. CONCLUSION Phenytoin loading by continuous IV infusion is an effective method of seizure suppression. It is important to identify patients at risk for serious cardiovascular side effects during such therapy. Despite a reduced rate of phenytoin infusion, patients in the present study with presumed or documented cardiovascular disease sustained significantly more side effects. No d e f i n i t e c o n c l u s i o n can be drawn about the cardiovascular interaction of phenytoin in individuals 141/53

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with known or presumed ASCVD, but this study adds credence to the concept that the administration rate should be reduced in such patients. All patients receiving IV phenytoin should be monitored closely. REFERENCES 1. Merrit HH, Putnam TJ: Sodium diphenylhydantoinate in the treatment of convulsive disorders. JAMA 1938;111:1068-1073. 2. Sacks C: Seizures and status epileptieus in adults, in Tintinall JE, Krome RL, Ruiz E leds): Emergency Medi cine: A Comprehensive S t u d y Guide. N e w York, McGraw-Hill, 1988, p 563-568. 3. Osborn HH, Zisfein J, Sparano R: Single-dose oral phenytoin loading. Ann Emerg Med 1987;16:407-412. 4. Cranford RE, Leppik IE, Patrick B, et ah Intravenous phenytoin: Clinical and pharmacokinetic aspects. Neurology 1978;28:874-880. 5. Cloyd JC, G u m n i t RJ, McLain LW: Status epilepticus, the role of i n t r a v e n o u s p h e n y t o i n . JAMA



CIII~ Chela 1988;34:B33-B39.

6. Earnest MP, Marx JA, Drury LR: Complications of intravenous phenytoin for acute treatment of seizures. lAMA 1983~249:762-765.

i4. Kullen LH, Orchard TJ: The epidemiology of atherosclerosis in 1987: Unraveling a common source epidemic. C]in Chem 1988;34:B40-B48.

7. Gal P, McCue JD, Tare M, et ah The beneficial effects of a phenytoin loading dose on seizure recurrence in patients with acute repetitive seizures: A preliminary report. N C Med J 1984;45:153-154.

15. Berensan GS, Srinivasan SR, Freedman DS, et ah A review of atherosclerosis and its evolution in childhood. A m J Med Sci 1987;294:429-440.

8. Goldschlager AW, Karliner JS: Ventricular standstill after intravenous diphenylhydantoin. A m Heart J I967;74:410-412. 9. Gellerman GL, Martinez C: Fatal ventricular fibrillation following intravenous sodium diphenylhydantoin therapy. JAMA 1967~200:337-338. 10. Unger AH, Aklaroff KH: Fatalities following intra~ venous use of sodium diphenylhydantoin for cardiac arrhythmias. ]AMA 1978;200:335-336. 11. Barron SA: Cardiac arrhythmias after a small IV dose of phenytoin. N Engl J Med 1976;275:678. 12. Kilarski DJ, Buchanan C, Von Behren L: Soft-tissue damage associated with intravenous phenytoin. N Eng] J Med 1984~311:1186-1187. 13. McGilI HC: The pathogenesis of atherosclerosis.

Annals of Emergency Medicine

16. Strong JP, Restrepo C, Guzman M: Coronary and aortic atherosclerosis in N e w Orleans. Lab Invest 1978;39:364 369. 17. Rubin E, Farhen JL: Pathology. Philadelphia, JB Lippincott Co, 1988, p 465. 18. Robbins SL, Lotran RS, Kumar V: P~tho]ogica] Basis of Disease. Philadelphia, WB 8aunders Co, 1984, p 508. 19. Cardueci B, Hedges JR, Bear JC, et al: Emergency phenytoin loading by constant intravenous infusion. Ann Emerg Med 1984;13:109,7-1031. 20. Eisner RF, Turnbull T, Howes DS, et ah Efficacy of a "standard" seizure workup in the emergency departmont. Ann Emerg Med 1986;156:33-39. 21. Louis S, Kott H, McDonelI F: The cardiocimnIatory changes caused by intravenous Dilantin and its solvent. A m Heart J 1967;74:523-529.

20:2 February 1991

Phenytoin administration by constant intravenous infusion: selective rates of administration.

To determine the adequacy of seizure control and the adverse effects of administering an IV loading dose of phenytoin by constant infusion pump...
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